Transdermal systems containing multilayer adhesive matrices to modify drug delivery

ABSTRACT

A transdermal drug-containing dosage unit comprises: a backing layer substantially impervious to the drug to be delivered transdermally; a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first delivery profile of the drug; a second polymeric adhesive matrix, in contact with said first polymeric adhesive matrix, having dispersed therein the drug and having a second delivery profile of the drug, wherein said second delivery profile is different from said first delivery profile; and a release liner in contact with the second polymeric adhesive matrix. 
     The first polymeric adhesive matrix can release the drug more quickly or more slowly than the second polymeric adhesive matrix. Through the selection of the two matrices, the delivery profile of the drug through the skin can be selectively modified and controlled.

This application is a divisional of U.S. Ser. No. 10,795,584, filed Mar.9, 2004. The prior application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to transdermal, pressure sensitive, adhesivedelivery systems for the delivery of an agent, such as a drug, throughthe skin. More specifically, this invention is directed to such systemswhich comprise multilayer adhesive matrices.

A well-known method of delivering certain drugs in a controlled mannerover time is through the use of a transdermal composition, such as apressure sensitive adhesive containing the drug. Known delivery systemsinvolve the incorporation of the desired drug into a carrier, such as apolymeric matrix and/or pressure sensitive adhesive formulation.Problems encountered with such delivery systems have includedinsufficient control over the rate and duration of the transdermalabsorption, and a variety of compositions have been developed in effortsto maximize control of the release of a desired drug and the efficacy ofthe delivery unit.

Although a number of commercially useful transdermal delivery systemshave been produced, further improvements are sought.

SUMMARY OF THE INVENTION

In accordance with the present invention, a transdermal drug-containingdosage unit comprises:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst initial delivery profile of the drug;

c) a second polymeric adhesive matrix, in contact with at least aportion of said first polymeric adhesive matrix, having dispersedtherein the drug and having a second delivery profile of the drug,wherein said second delivery profile is different from said firstdelivery profile; and

d) a removable release liner in contact with at least a portion of thesecond polymeric adhesive matrix.

The invention further comprises a method for administering a drugtransdermally to an individual in need of such administration,comprising applying to the skin of the individual a transdermal dosageunit comprising:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst initial delivery profile of the drug; and

c) a second polymeric adhesive matrix, in contact with at least aportion of said first polymeric adhesive matrix, having dispersedtherein the drug and having a second delivery profile of the drug,wherein said second delivery profile is different from said firstdelivery profile.

The first polymeric adhesive matrix can release the drug more quickly ormore slowly than the second polymeric adhesive matrix. Through theselection of the two matrices, the delivery profile of the drug throughthe skin can be selectively modified and controlled to an extent notpossible with delivery devices which comprise only a single adhesivematrix.

If desired, the compositions further can contain or employ otheringredients known for use in pressure sensitive adhesives, includingcrosslinking agents, plasticizers, tackifiers, fillers, anti-oxidantsand excipients or penetration enhancers.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the transdermal flux (rate of delivery) ofthree matrices, including a bi-layer matrix in accordance with thisinvention.

FIG. 2 is a graph showing the cumulative delivery of the three matricesof FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to dermal compositions suitable for thedelivery of a drug through the skin. The compositions allow for verycontrolled delivery of the drug through the unique combination of two ormore different adhesive matrices which can be selected and layered toprovide a desired drug delivery profile.

Specifically, compositions of the present invention comprise:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst delivery profile of the drug;

c) a second polymeric adhesive matrix, in contact with a portion of saidfirst polymeric adhesive matrix, having dispersed therein the drug andhaving a second delivery profile of the drug; and

d) a removable release liner in contact with at least a portion of thesecond polymeric adhesive matrix.

The first and second polymeric adhesive matrices in a two matriccomposition also will be referred to as the anchor adhesive layer andthe skin contact adhesive layer, respectively. They are selected suchthat there is a significant difference in the rate of drug delivery fromeach layer. In addition, the two adhesives also can be selected suchthat there is a significant difference in one or more other physicalcharacteristics, such as the solubility, miscibility or stability of thedrug or desired excipients, in each of the two layers, which can furtheraffect the delivery of the drug from the composition and through theskin of the person wearing the composition. As used herein, “significantdifference” means a difference in drug delivery of at least about10%-100%, preferably at least about 15%-60%, between the two adhesivematrices or layers. The desired difference in drug delivery ratesbetween the two layers can be achieved simply through the selection ofthe two adhesive matrices or through the selection of the adhesive foreach matrix in combination with the choice of relative thickness of eachlayer.

The first and second adhesive matrices can be selected such that therate of drug delivery initially is faster from the second matrix, orskin contact layer, than it is from the first matrix, or anchor layer.In such instances, there will be an initial burst, or spike, of drugdelivered through the skin of the wearer, followed by a slower and moresteady release of the drug. Alternatively, the adhesive matrices can beselected such that the rate of drug delivery initially is faster fromthe first matrix, or anchor layer, than it is from the second matrix, orskin contact layer. Such a system allows for the tuning of the deliveryprofile depending upon the thickness of the two layers. Specifically,the slower delivering adhesive layer contacting the skin controls thedelivery through the skin and modulates the faster delivering adhesivelayer's tendency to deliver the drug rapidly. In such instances, therewill be a continuous drug delivery, perhaps with a “burst” in deliveryat a specific time post-application, depending upon the thickness andcomposition of the matrices and the drug concentration. For instance,the burst could be accounted for by a release of drug and components bythe anchor layer having a driving force so great as to overcome any ratelimiting properties that the skin contact layer may have. Such a releasepattern is useful, for example, in delivering drugs to the body to mimica circadian rhythm (e.g., testosterone).

The rate of release from an adhesive matrix can change over the courseof its functional lifespan. Often, this is caused by the absorption ofwater or other components from the surface of the skin of the wearer.Alternatively, one can incorporate into the skin contact matrix anexhaustible penetration retardant or load the skin contact matrix withsolid drug crystals to impair initial delivery of the drug through theskin.

In one embodiment of this invention, the composition comprises more thantwo adhesive matrices, such as three or four or five adhesive matrices.For example, a composition could comprise one or more additionaladhesive matrices sandwiched in between the adhesive matrix which is incontact with the backing layer, and the adhesive matrix which is incontact with the release liner. An advantage to including three or morematrices is having increased ability to control the rate of deliveryeither through the use of the different layers or by adding differentexcipients to the different layers to change or control the rate ofdelivery. Other advantages include increased chemical stability,processing, cosmetic or physical (improved wear) advantages. If thereare more than two adhesive matrixes in a composition, the initial rateof delivery of the drug from one of the matrices is different from thatfrom at least one of the other matrices. In one embodiment, the initialrate of drug delivery in each matrix is different from that of eachother matrix.

The adhesives used in the compositions, or unit dosage forms, of thepresent invention are those which are tacky or sticky to the touch andwhich typically adhere to a substrate, such as the skin, upon theapplication of mild pressure. They therefore often are referred to aspressure sensitive adhesives.

The choice for each adhesive matrix layer can be made from any pressuresensitive adhesives conventionally used in transdermal delivery devices,provided that the two materials chosen have significantly different drugdelivery rates. In one preferred embodiment, one matrix comprises anacrylic adhesive and the other matrix comprises a silicone adhesive. Inthis combination, the acrylic adhesive has the relatively slow deliverycharacteristics; the silicone adhesive has the more rapid deliverycharacteristics. In a second preferred embodiment, one matrix comprisesan acrylic adhesive and the other comprises a polyisobutylene adhesive.In this embodiment, the acrylic adhesive again has the relatively slowdelivery characteristics; the polyisobutylene adhesive delivers the drugmore rapidly.

If the composition comprises three adhesive matrices, it can comprise,for example, an acrylic adhesive layer sandwiched between two siliconeadhesive layers, or a silicone adhesive layer in between two acrylicadhesive layers. Alternatively, each layer could have a differentpolymer, such as a silicone, polyisobutylene, and acrylate adhesivemultilayer system. The choice of adhesive for each layer will bedetermined by the delivery profile desired for the final composition.

Suitable silicone adhesives include pressure sensitive adhesives madefrom silicone polymer and resin. The polymer to resin ratio can bevaried to achieve different levels of tack. Specific examples of usefulsilicone adhesives which are commercially available include the standardBIOPSA® series (7-4400, 7-4500 and 7-4600 series) and the aminecompatible (endcapped) BIOPSA® series (7-4100, 7-4200 and 7-4300 series)manufactured by Dow Corning. Preferred adhesives include BIO-PSA®7-4202, BIO-PSA® 7-4301, BIO-PSA® 7-4302, BIO-PSA® 7-4501, BIO-PSA®7-4502 and BIO-PSA® 7-4602.

Suitable polyisobutylene adhesives are those which are pressuresensitive and have suitable tack. The polyisobutylene can comprise amixture of high and low molecular weight polyisobutylenes. Specifically,high molecular weight polyisobutylenes are those with a molecular weightof at least 1,000,000. Low molecular weight polyisobutylenes are thosewith a molecular weight of at least 100 but less than 1,000,000.Desirably, the high molecular weight polyisobutylene comprise betweenabout 20 and 80% by weight of the total polyisobutylene, preferablybetween about 40% and 50%, most preferably about 45%, and the lowmolecular weight polyisobutylene comprises between about 80% and 20% byweight of the total polyisobutylene, preferably between about 50% and60%, most preferably about 55%. A specific example of a usefulpolyisobutylene is one which comprises 45% high molecular weight polymer(˜1,250,000) and 55% low molecular weight polymer (˜44,000) atapproximately 25% solids in n-heptane.

Useful acrylic polymers include various homopolymers, copolymers,terpolymers and the like of acrylic acids. They include copolymers ofalkyl acrylates or methacrylates. Polyacrylates include acrylic acid,methacrylic acid, N-butyl acrylate, n-butyl methacrylate, hexylacrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate. Useful acrylic adhesives include crosslinked carboxylfunctional adhesives such as DURO-TAK®87-2194, non-crosslinked carboxylfunctional adhesives such as DURO-TAK®87-2051, crosslinked hydroxylfunctional adhesives such as DURO-TAK®87-2516, non-crosslinked hydroxylfunctional adhesives such as DURO-TAK®87-2287, grafted adhesives such asDURO-TAK®87-5298 and non-functional adhesives such as DURO-TAK®87-4098.Preferred acrylic adhesives include crosslinked carboxyl functionalacrylic adhesives, such as DURO-TAK® 87-2194 manufactured by NationalStarch and Chemical Co.

In addition to the aforementioned adhesives, other adhesives useful incompositions in accordance with this invention include other acrylate,rubber or silicone pressure adhesives, whether hotmelt, waterborne orsolvent based.

In addition to the two or more adhesive layers, compositions inaccordance with this invention comprise a backing and a release liner,each of which can comprise materials conventionally used in transdermalpatch compositions. The material chosen for the backing is one which isflexible, impermeable to the drug, and, if desired, can be colored orlabeled. The backing provides support and a protective covering for thedosage unit. Suitable backing materials include those known in the artfor use with pressure sensitive adhesives. For example, the backing cancomprise a polyolefin, polyester, multi-layer EVA film and polyester,polyurethane or combination thereof. A preferred backing material isMEDIFLEX® 1000, a polyolefin manufactured by Mylan Technologies, Inc.

The release liner is removed and discarded from the composition toexpose the skin contact adhesive layer which functions as the means ofapplying the composition to the patient and through which the drugpasses as it is delivered to the patient. Suitable release linersinclude those known in the art for use with pressure sensitive adhesivecompositions. For example, the release liner can comprise afluorosilicone coated polyester or silicone coated polyester. Apreferred release liner is MEDIRELEASE® 2500, MEDIRELEASE® 2249 andMEDIRELEASE® MR2226, each manufactured by Mylan Technologies, Inc., orScotchpak® 1022, manufactured by 3M Pharmaceuticals/D.D.S. The releaseliner can, however, comprise other materials, including paper orpaper-containing layers or laminates, various thermoplastics, polyesterfilms, foil liners, and the like.

Once the dosage unit forms have been prepared, they are placed inappropriate packaging for storage until they are to be applied intransdermal treatment.

The compositions of this invention possess sufficient adhesiveproperties that once the release liner is removed and the composition isapplied to the skin the composition can remain in place for a period oftime sufficient to distribute the desired amount of the drug containedtherein with a low incidence of debonding.

The compositions of this invention can be made by first preparingseparate adhesive blends for each layer of the dosage unit, thendissolving or suspending the drug of choice in at least one of theblends, each of which has been made by mixing a suitable solvent withthe pressure sensitive adhesive of choice. The anchor layer is coatedfirst on a release liner, dried and then laminated to the desiredbacking film, according to predetermined parameters, such as temperatureand dwell time (line speed), which yield minimal residual solventlevels. The skin contact layer then is coated on a separate releaseliner and dried. The release liner is removed from the anchor layer andthe adhesive side of the skin contact layer is laminated onto theadhesive side of the anchor layer so that the anchor layer is betweenthe backing and the skin contact layer. If the drug initially issuspended or dissolved in only one of the two adhesive layers, it will,over time, equilibrate into the other adhesive layer until a commonequilibrium is achieved. It may be desirable to prepare the compositionwith the drug initially suspended or dispersed in only one of the twoadhesive layers if, for example, the other adhesive layer is preparedwith a solvent which would be deleterious to the drug but whichevaporates during processing (coating and drying).

If more than two layers are to be provided, the third (middle) layer iscoated as a liquid onto a release liner, dried, laminated to either theadhesive side of the dried skin contact layer or the adhesive side ofthe dried anchor layer once the release liner has been removed from thelatter, then the two parts of the dosage unit are laminated to oneanother as above.

Suitable solvents for use in preparing the adhesive blends includeacetone, heptane, ethyl acetate, isopropanol, ethanol, hexane, toluene,xylene, 2,4-pentanedione, methanol and water.

Alternative methods for producing or achieving a transdermal deliverydosage unit in accordance with this invention may be apparent to personsskilled in the art, and such alternative methods also fall within thescope of the present invention. For example, an adhesive blend can becoated onto the backing film rather than the release liner.Alternatively, an adhesive coating can be created without using asolvent, such by heating the adhesive to its melting temperature(hot-melt adhesive). With this technique, no drying of the adhesive isrequired, only cooling.

There are many coating techniques for applying a continuous liquidcoating onto a substrate, including using a gravure roll, reverse roll,falling film, inkjet, etc. All of these are well-known to persons ofordinary skill in the art and can be used to create pressure-sensitiveadhesive layers from a solvated blend. Alternatively, a thin adhesivecoating can be achieved by extrusion, in which the adhesive blend isforced through a die under pressure onto the substrate either as acontinuous coating or as a printed (intermittent) pattern.

The thickness of the anchor and skin contact layers of the compositionsof this invention can vary, depending upon such factors as the amount ofdrug to be delivered from the composition and the desired wear period.Generally, however, the skin contact layer has a thickness of betweenabout 5 and 150 gsm, preferably between about 25 and 50 gsm. The anchorlayer generally has a thickness of between about 5 and 150 gsm,preferably between about 25 and 100 gsm. Variations can be determined asa matter of routine experimentation by those of ordinary skill in theart.

The compositions of the present invention are suitable for thetransdermal delivery of a wide range of drugs. The term “drugs” isintended to have its broadest interpretation as including anytherapeutically, prophylactically and/or pharmacologically orphysiologically beneficial active substance, or a mixture thereof, whichis delivered to a living being to produce a desired, beneficial effect.More specifically, any drug which can produce a pharmacologicalresponse, localized or systemic, whether therapeutic, diagnostic, orprophylactic in nature, is within the contemplation of the presentinvention. Also included within the scope of the invention are bioactiveagents, such as insect repellants, sun screens, cosmetic agents, etc.The drug can be provided in an amount sufficient to cure, diagnose, ortreat a disease or other condition. This definition includes, but is notlimited to:

1. cardiovascular drugs, such as nitroglycerin, propranolol, isosorbidedinitrate, isosorbide mononitrates, diltiazem, nifedipine, procainamide,clonidine and others,

2. androgenic steroids, such as testosterone, methyltestosterone andfluoxymesterone,

3. estrogens, such as conjugated estrogens, esterified estrogens,etropipate, 17-β estradiol, 17-β estradiol valerate, equilin, mestranol,estrone, estriol and diethylstilbestrol,

4. progestational agents, such as progesterone, 19-norprogesterone,norethindrone, norethindrone acetate, melengestrol chloradinone,ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate,norethynodrel, dimethisterone, ethinylestrenol, norgestrel,megestrolacetate, and ethinodiol diacetate,

5. drugs which act on the central nervous system, including sedatives,hypnotics, analgesics, anesthetics, and antianxiety agents; such assalicylic acid derivatives, opiates, opioids and the like; includingchloral hydrate, benzodiazepines, naloxone, haloperidol, pentobarbitol,phenobarbitol, secobarbital, codeine, lidocaine, dibucaine, benzocaine,fentanyl, fentanyl analogs and nicotine,

6. nutritional agents, including vitamins, essential amino acids andessential fats,

7. anti-inflammatory agents, including hydrocortisone, cortisone,dexamethasone, prednisolone, prednisone, halcinonide,methylprednisolone, fluorocortisone, corticosterone, paramethasone,ibuprofen, naproxen, fenoprofen, fenbufen, indoprofen, salicylic acid,methyl salicylate, sulindac, mefenamic acid, piroxicam, indonisilone andtolmetin,

8. antihistamines, such as diphenhydramine, triprolidine,chlorcyclizine, promethazine, cyclizine, chlorprenaline, terrenadine,phenylpropanolamine and chlorpheniramine,

9. miotics, such as pilocarpine,

10. dermatological agents, such as vitamins A and E,

11. anti-spamodics, including atropine, methantheline, papverine,cinnmedrine and methscopolamine,

12. anti-depressants, such as isocaboxazid, phenelzine, imipramine,amitrptyline, trimepramine, dozepin, desipramine, nortriptyline,protriptyline, amoxapine and maprotiline,

13. anti-cancer drugs,

14. anti-diabetics, such as insulin,

15. anti-estrogens or hormone agents, including tamoxifen or HCG,

16. anti-infectives, including antibiotics, anti-bacterials andanti-virals, such as tetracycline, chloramphenicol, sulfacetamide,sulfadiazine, sulfamerazine, sulfoxazole, idoxuridine, and erythromycin,

17. anti-allergenics, such as antazoline, metapyrilene, and pyrilamine,

18. anti-pyretics, including aspirin and salicylamide,

19. anti-migraine agents, including dihydroergotamine and pizotyline,

20. tranquilizers, including reserpine, chlorpromazine, and antianxietybenzodiazepines, and

21. anti-psychotic agents, including haloperidol loxapine, molindone,thiothixene, pimozide, risperidone, quetiapine fumarate, olanzapine,and/phenothiazine derivatives.

Other drugs suitable for delivery using a transdermal system can bereadily determined by persons of ordinary skill in the art. In addition,pharmacologically acceptable derivatives of the drugs, such as ethers,esters, amides, acetals, salts and the like, which are suitable fortransdermal administration can be used.

In a preferred embodiment, a composition of this invention comprisesestradiol, a combination of estradiol and norethindrone acetate or acombination of estradiol and levonorgestrel or other progestin. Suchpatches are indicated for post-menopausal women as hormone replacementtherapy. One or more bioactive and biocompatible derivatives ofestradiol capable of being absorbed transdermally can be used in placeof, or in combination with, estradiol. Derivatives of estradiol include13- or 7-mono-esters and di-esters of estradiol, includingestradiol-3,17-diacetate; estradiol-17-acetate; estradiol-3,17-valerate;estradiol-3-valerate; estradiol-17-valerate; 3-mono-17-mono- and3,17-dipilivate esters; 3-mono-, 17-mono-, and 3,17-dipropionate esters;corresponding heptanoate and benzoate esters; ethanol estradiol;estrone; and other estrogenic steroids and derivatives which aretransdermally absorbable.

Other suitable progestins include progesterone, medroxyprogesteroneacetate, ethynodiol diacetate, and the like.

When estradiol is used as the sole active drug in the dosage unit, eachunit typically comprises from about 0.1% to about 4.0% (w/w) estradiol.When estradiol is provided in combination with either norethindrone orlevonorgestrel or other progestin, each dosage unit typically comprisesabout 0.1% to about 4.0% (w/w) estradiol and about 0.1% to about 20% ofthe progestin. These ranges are intended only as guidelines; the actualamount of drug provided depends upon the choice of adhesive for the skincontact and anchor layers, the amount of drug desired to be deliveredtransdermally to the patient within a certain period of time, and therate at which the drug can permeate through the skin of the personwearing the dosage unit or patch.

In one specific embodiment of this invention, a transdermal dosage unitcomprises a silicone skin contact layer of about 25 gsm (grams/m²) andan acrylate anchor layer of about 75 gsm and contains about 1.4% (w/w)estradiol. In a second specific embodiment, a transdermal dosage unitcomprises a silicone skin contact layer of about 50 gsm and an acrylateanchor layer of about 75 gsm and contains about 1.4% estradiol. In athird specific embodiment, a transdermal dosage unit comprises asilicone skin contact layer of about 25 gsm and an acrylate anchor layerof about 100 gsm, each containing about 1.4% estradiol.

In a fourth specific embodiment, a transdermal dosage unit comprises apolyisobutylene skin contact layer of about 50 gsm which contains 1.0%(w/w) estradiol and a 50 gsm anchor layer which contains about 1.4%(w/w) estradiol in an acrylate adhesive.

The amount of drug to be incorporated into the compositions of thisinvention vary, depending upon the drug or combination of drugs ofinterest, the desired therapeutic effect and the time span over whichthe composition will release the drug and provide therapy. As thepassage of drugs through the skin often is the rate limiting step, theamount of drug chosen and the rate of release from the adhesivestypically are selected so as to provide for delivery of the drug for aprolonged period of time, wherein the minimum amount of the drug in thesystem is based upon the rate at which it will pass through the skin inthe time period for which the composition is to provide therapy. Theamount of drug in the composition typically can vary from about 0.05% toabout 40% by weight of the delivery device and preferably is within therange of about 0.1% to about 20% by weight, most preferably within therange of about 0.1% to about 4.0% by weight.

The drug(s) of interest can be provided in admixture with otheringredients which are compatible with the transdermal administration ofthe desired drug to patients. Such other ingredients includecrosslinking agents, plasticizers, tackifiers, fillers, anti-oxidants,dispersing agents and excipients, such as propylene glycol.

The invention is further illustrated by the following examples, whichare not to be construed as limiting.

EXAMPLES Example 1 Preparation of a Two-Layer Delivery Device

Separate adhesive blends are made for each layer of the finished system,with the drug dissolved or suspended in at least one blend. The blendsare made by suspending or dissolving the drug in a combination ofsolvent, adhesive, and, optionally, excipient. Desired remainingcomponents for each blend can be dispersed in a premix or added directlyto the adhesive blends along with the drug. Once all the components areadded together in their respective blend, the blends are mixedseparately with an air driven mixer until uniform. See Table 1 below forexample amounts of each component blend:

TABLE 1 Component % (w/w) Wet Weight (g) Anchor Layer Blend EthylAlcohol Dehydrated 4.56 9.50 Alcohol USP-200 Proof punctilious (EthylAlcohol) Estradiol Hemihydrate, USP, micronized 0.63 1.32 Povidone USP(Plasdone K-29/32) 1.55 3.23 DURO-TAK ® 87-2194 93.25 194.14 SkinContact Layer Blend Ethyl Alcohol Dehydrated 5.89 6.00 Alcohol USP-200Proof punctilious (Ethyl Alcohol) Estradiol Hemihydrate, USP, micronized0.81 0.83 Povidone USP (Plasdone K-29/32) 2.00 2.04 360 Medical Fluid(100 cSt.) 2.94 3.00 BIO-PSA ®7-4502 88.36 90.08

Following thorough mixing, the anchor layer blend is coated onto anappropriate release liner at the specified thickness to obtain thedesired gsm. The laminate is dried for 4 minutes at 41° C. followed by 4minutes at 77° C. in forced air ovens, then laminated to the desiredbacking film. The skin contact layer blend is coated onto a separaterelease liner and dried, using the same conditions as were used toprepare the anchor layer laminate.

To assemble the finished product, the anchor layer release liner isremoved and the adhesive side of the dried skin contact layer islaminated to the adhesive side of the anchor layer.

Example 2

Transdermal delivery devices were made in accordance with the teachingsof Example 1. Each device contained a total of 0.1-4.0% (w/w) drug. Theanchor adhesive matrix of each delivery device was an acrylicpressure-sensitive adhesive and initially contained 0.1%-4.0% drug andbetween 0-5.0% (w/w) povidone. The skin contact matrix of each deliverydevice comprised a silicone pressure-sensitive adhesive and initiallycontained 0.1% to 4.0% of the drug, 0-5% (w/w) povidone and 0-5% of atackifier/plasticizer. The silicone contact layer of each device had athickness of 5-100 gsm and the anchor layer had a thickness of 5-150gsm. In one embodiment, the device comprised 1.4% estradiol in each ofthe acrylic adhesive layer and the skin contact layer, 3.4% povidone ineach of the acrylic adhesive layer and the skin contact layer, and theskin contact layer comprised 5% of 360 Medical Fluid (100 cSt) as thetackifier/plasticizer.

Example 3

Transdermal delivery devices were made in accordance with the teachingsof Example 1. Each device contained a total of 0.1-4.0% (w/w) drug. Theanchor adhesive matrix of each delivery device was an acrylicpressure-sensitive adhesive and initially contained 1.4% drug andbetween 0-5.0% (w/w) povidone. The anchor layer also contained 0-10%(w/w) propylene glycol. The skin contact matrix of each delivery devicecomprised a polyisobutylene pressure-sensitive adhesive and initiallycontained 1.0% drug, 0-5% (w/w) povidone and 10-50% of atackifier/plasticizer. In each device, the skin contact layer had athickness of 5-100 gsm and the anchor layer had a thickness of 5-100gsm. In one embodiment, the device comprised 3.4% povidone in each ofthe acrylic adhesive layer and the skin contact layer, and the skincontact layer comprised 30% mineral oil as the tackifier/plasticizer.

Example 4

A transdermal device was made in accordance with the teachings ofExample 2. The silicone skin contact layer had a thickness of 25 gsm andthe anchor layer had a thickness of 75 gsm.

Example 5

A transdermal device was made in accordance with the teachings ofExample 2. The silicone skin contact layer had a thickness of 50 gsm andthe anchor layer had a thickness of 75 gsm.

Example 6

A transdermal delivery device was made in accordance with the teachingsof Example 3. The polyisobutylene skin contact layer had a thickness of50 gsm and the acrylate anchor layer had a thickness of 50 gsm.

Example 7

Transdermal delivery devices were made in accordance with the teachingsof each of Examples 2 and 3. In each device, the drug was estradiol, acombination of estradiol and norethindrone acetate or a combination ofestradiol and levonorgestrel.

Example 8

Transdermal delivery devices were made in accordance with the teachingsof Example 2. In each device, the silicon adhesive was BIO-PSA® 7-4202,7-4301, 7-4302, 7-4501, 7-4502 or 7-4602.

Example 9

Transdermal delivery devices were made in accordance with the teachingsof Example 3. In each device, the polyisobutylene adhesive comprisedfrom 20-80% of polyisobutylene with a molecular weight of at least1,000,000 and 80-20% of polyisobutylene with a molecular weight ofbetween 100 and 1,000,000.

Example 10

Transdermal delivery devices were made in accordance with the teachingsof Example 9. In each device, the polyisobutylene adhesive comprised 45%polyisobutylene with a molecular weight of at least 1,000,000 and 55%polyisobutylene with a molecular weight of between 100 and 1,000,000.

Example 11

A transdermal delivery device was made in accordance with the teachingsof Example 2. The 50 gsm skin contact layer contained 1.4% estradiolhemihydrate, 3.4% povidone and 5% 360 Medical Fluid (100 cSt) in amedical grade, silicone pressure sensitive adhesive BIO-PSA® 7-4502. The75 gsm anchor layer contained 1.4% estradiol hemihydrate and 3.4%povidone in DURO-TAK® 87-2194, a medical grade acrylate pressuresensitive adhesive. The backing consisted of polyolefin (MEDIFLEX®1000). The release liner was fluorosilicone coated polyester(MEDIRELEASE® 2500 or Scotchpak® 1022). All percentages are w/w.

The delivery system had a size of 30 cm², produced a delivery spike ofestradiol and delivered approximately 0.1 mg/day in vitro.

Example 12

A transdermal delivery device was made in accordance with the teachingsof Example 3. The 50 gsm skin contact layer contained 1.0% estradiolhemihydrate, 3.4% povidone and 30% mineral oil in medical gradepolyisobutylene pressure sensitive adhesive. The 50 gsm anchor layercontained 1.37% estradiol hemihydrate, 8.0% propylene glycol and 3.4%povidone in DURO-TAK® 87-2194, a medical grade acrylate pressuresensitive adhesive. The backing consisted of polyolefin (MEDIFLEX®1000). The release liner was siliconized polyester (MEDIRELEASE® 2249).All percentages are given on a w/w basis.

The delivery device had a size of 30 cm², produced a delivery spike ofestradiol and delivered 0.1 mg/day in vitro.

Example 13

A transdermal delivery device was made in accordance with the teachingsof Example 1. The anchor layer matrix comprised 50 gsm DURO-TAK® 87-2194to which was laminated a 50 gsm polyisobutylene skin contact layermatrix. The anchor layer matrix contained 1.37% estradiol hemihydrate,4.0% propylene glycol, 3.4% povidone and 1.13% colloidal silicondioxide. The skin contact layer matrix contained 1.37% estradiolhemihydrate, 3.4% povidone, 4.0% propylene glycol, 1.13% colloidalsilicon dioxide, and 30% mineral oil in a polyisobutylene adhesive. Thebacking was MEDIFLEX® 1000 and the release liner was MEDIRELEASE® 2226.

Example 14

A transdermal delivery device was made in accordance with the teachingsof Example 1. The anchor layer matrix comprised 75 gsm DURO-TAK® 87-2194to which was laminated a 50 gsm skin contact layer matrix of BIO-PSA®7-4502. The anchor layer matrix contained 1.37% estradiol hemihydrateand 3.4% povidone. The skin contact layer matrix contained 1.37%estradiol hemihydrate, 3.4% povidone and 5% 360 Medical Fluid (100 cSt).The backing was MEDIFLEX® 1000 and the release liner was MEDIRELEASE®2500.

Example 15

A delivery device was made in which the rate of delivery of drug fromthe skin contact layer was slower than the rate of release from theanchor layer. The transdermal delivery profiles of the bilayer andconstitutive monolayers show that the bi-layer delivers drug through theskin at the same normalized rate as the rapidly delivering (silicone)matric, but at a steady rate characteristic of the slow-delivery(acrylic) matrix.

Rapidly delivering adhesive films were prepared by coating a siliconeadhesive blend so as to create a homogeneous dry adhesive layercontaining 1.25% estradiol, 5% polyvinyl pyrrolidone, 4% oleic acid, andBIO-PSA® 7-4502 silicone adhesive. The blend was coated onto 3MScotchPak® 1022 release liner and dried for 4 minutes at 41° C. and 4minutes at 77° C. to create adhesive films of approximately 100 gramsper square meter (gsm).

Slowly delivering adhesive films were prepared by coating an acrylicadhesive blend so as to create a homogeneous dry adhesive layercontaining 1.25% estradiol, 5% polyvinyl pyrolidone, 4% oleic acid andDURO-TAK® 87-2516 acrylic adhesive from National Starch and Chemical Co.The blend was coated onto MEDIRELEASE® 2249 release liner and dried for4 minutes at 40° C. and 4 minutes at 77° C. to create two dry adhesivefilms of approximately 25 and 100 gsm, respectively.

Two drug delivery systems were prepared by laminating either the 100 gsmrapidly delivering silicone adhesive film or the 100 gsm slowlydelivering acrylic adhesive film to 3M CoTran 9722 backing film.

A third drug delivery system was prepared by first transferring therapidly delivering silicone adhesive film from the release liner to 3MCoTran 9722 backing film. The 25 gsm slowly delivering acrylic adhesivefilm was laminated on top of the rapidly delivering silicone adhesivefilm. The finished system consisted of a backing film, 100 gsm siliconeadhesive layer, 25 gsm acrylic adhesive layer and release liner. Afterallowing all systems to equilibrate, they were tested for in vitrodelivery of drug through human skin. The table below summarizes thethree systems tested:

System 3 (Bi-Layer System 1 (Rapidly System 2 (Slowly with SlowlyDelivering Delivering Silicone Delivering Acrylic Acrylic Matrix inAdhesive Matrix) Matrix) Contact with Skin) GSM: 100 GSM: 100 AcrylicGSM: 25 Silicone GSM: 100 Estradiol 1.25% Estradiol 1.25% Estradiol1.25% PVP 5% PVP 5% PVP 5% Oleic Acid 4% Oleic Acid 4% Oleic Acid 4%By laminating the two layers together, the resulting transdermal systemdelivered the medication through the skin at the same normalized rate asthe rapidly-delivering matrix, but at a steady continuous rate morecharacteristic of the slowly-delivering matrix. See FIGS. 1 and 2.

1. The transdermal drug-containing dosage unit of claim 37, wherein saiddrug comprises a cardiovascular drug, an androgenic steroid, anestrogen, a progestational agent, a drug which acts on the centralnervous system, a nutritional agent, an anti-inflammatory agent, anantihistamine, a miotic, a dermatological agent, an anti-spasmodic, ananti-depressant, an anti-cancer drug, an anti-diabetic, ananti-estrogen, an anti-psychotic, an anti-infective agent, ananti-allergenic, an anti-pyretic, an anti-migraine agent or atranquilizer.
 2. The transdermal drug-containing dosage unit of claim37, wherein said drug comprises an estrogen or a combination of anestrogen and a progestin.
 3. The transdermal drug-containing dosage unitof claim 2, wherein said estrogen comprises estradiol or mono- ordi-esters thereof which are transdermally absorbable.
 4. The transdermaldrug-containing dosage unit of claim 2, wherein said progestin comprisesnorethindrone acetate or levonorgestrel.
 5. The transdermaldrug-containing dosage unit of claim 37 which comprises from about 0.05%to about 40% w/w of drug.
 6. The transdermal drug-containing dosage unitof claim 5, which comprises from about 0.1% to about 4.0% w/w of drug.7. The transdermal drug-containing dosage unit of claim 2, whichcomprises from about 0.1% to about 4.0% of said estrogen.
 8. Thetransdermal drug-containing dosage unit of claim 7, which furthercomprises from about 0.1% to about 20% of a progestin.
 9. A method foradministering a drug transdermally to an individual in need of suchadministration, comprising applying to skin of the individual atransdermal dosage unit comprising: a) a backing layer substantiallyimpervious to the drug to be delivered transdermally; b) a firstpolymeric adhesive matrix, in contact with the backing layer, havingdispersed therein the drug and having a first initial rate of deliveryof the drug; c) a second polymeric adhesive matrix, having dispersedtherein the drug and having a second initial rate of delivery of thedrug which is different from said first rate of delivery; and d) atleast one additional polymeric adhesive matrix sandwiched between saidfirst and second polymeric matrices, each said additional adhesivematrix having an initial rate of delivery of the drug; wherein saidinitial rate of delivery of each of said matrices is different from oneanother.
 10. A transdermal delivery device for the transdermal deliveryof an active substance, for example a pharmacologically activesubstance, the device having first and second superimposed mutuallycontacting adhesive layers, of which said first layer is pressuresensitive adhesive and is in use brought into contact with the skin, theactive substance being dissolved in both said layers, wherein theaffinity of said first layer for said active substance is between about1.15 and about 10 times lower than that of said second layer, thepercent saturation of said active substance in both said layers beingthe same and being less than 100%, said first layer having a greaterthickness than said second layer.
 11. A transdermal delivery deviceaccording to claim 10, wherein the ratio of the thickness of the firstlayer to the thickness of the second layer is in the range 1.2 to
 7. 12.A transdermal delivery device according to claim 10, wherein thethickness of each said layer when dry is in the range 5 to 150 μm.
 13. Atransdermal delivery device according to claim 12, wherein the thicknessof the first layer when dry is in the range 5 to 125 μm and thethickness of the second layer when dry is in the range 5 to 75 μm.
 14. Atransdermal delivery device according to claim 10 wherein the affinityof said first layer for said active substance is 1.15 to 1.75 timeslower than that of said second layer.
 15. A transdermal delivery deviceaccording to claim 10 wherein said first layer has a polymer matrixconsisting substantially of at least one non-functional polymercomponent and said second layer has a polymer matrix consisting of atleast one functional polymer component or a mixture of functional andnon-functional polymer components.
 16. A transdermal delivery deviceaccording to claim 15 wherein said second layer is composed of about 10to about 90% of at least one functional polymer component and about 90to about 10% of at least one non-functional polymer component,percentages being expressed relative to total weight of dry layer.
 17. Atransdermal delivery device according to claim 16 wherein said secondlayer is composed of about 20 to about 50% of at least one functionalpolymer component and about 50 to about 80% of at least onenon-functional polymer component, percentages being expressed relativeto total weight of dry layer.
 18. A transdermal delivery deviceaccording to claim 15 wherein the or each said functional polymercomponent of said second layer has functional groups selected from —COOHand —OH.
 19. A transdermal delivery device according to claim 10 whereinsaid first and second layers are composed of polymer components selectedfrom acrylic polymers, polyisobutylenes and silicone elastomers.
 20. Atransdermal delivery device according to claim 10 wherein each saidlayer is composed of one or more acrylic polymer components.
 21. Atransdermal delivery device according to claim 10 wherein at least oneof the first and second layers comprises at least one permeationenhancer.
 22. A transdermal delivery device according to claim 10wherein the amount of permeation enhancer in each of said layers,expressed as percent of the dry weight of each layer, is between 3.5 and22%.
 23. A transdermal delivery device according to claim 10 wherein thepharmacologically active substance is selected from fentanyl,alfentanyl, sufentanyl, carfentanyl, lofentanyl, buprenorphine and thederivatives and pharmaceutically acceptable salts thereof.
 24. Atransdermal delivery device according to claim 10 wherein thepharmacologically active substance is nicotine or one of itspharmaceutically acceptable salts and derivatives.
 25. A transdermaldelivery device according to claim 10 wherein the pharmacologicallyactive substance is fentanyl or one of its pharmaceutically acceptablesalts or derivatives.
 26. A transdermal delivery device according toclaim 25 wherein the first layer to be in intimate contact with the skinhas an initial fentanyl base content of 2 to 4%, expressed as percentageof the dry weight of said first layer.
 27. A transdermal delivery deviceaccording to claim 25 wherein the second layer has an initial fentanylbase content of 4 to 10%, expressed as percentage of the dry weight ofsaid second layer.
 28. A transdermal delivery device according to claim25, adapted to release a therapeutically effective dose of the activesubstance during at least three days.
 29. A process for the manufactureof a device for the transdermal administration of an active substanceaccording to claim 10, which comprises the following steps: (a) coatingand drying a first precursor adhesive layer that will be the secondlayer of said device onto a temporary release liner; (b) laminating saidfirst precursor adhesive layer together with the temporary release filmonto a backing layer; (c) coating and laminating onto a final releaseliner a second precursor adhesive layer that will be the first layer ofsaid device; and (d) detaching the temporary release film and laminatingsaid second precursor adhesive layer adhered to the final release linerobtained in {circle around (c)}) to said first precursor adhesive layerobtained in (b) that is adhered to the backing layer.
 30. A processaccording to claim 29, wherein the respective amounts of said activesubstance in said first and second precursor adhesive layers differ fromthe amounts in said device when ready for use, and after step (d) theactive substance is allowed to equilibrate its percent saturationbetween the respective layers.
 31. A transdermal delivery device for thetransdermal delivery of an active substance, for example apharmacologically active substance, the device having first and secondsuperimposed mutually contacting adhesive layers, of which said firstlayer is pressure sensitive adhesive and is in use brought into contactwith the skin, the active substance being dissolved in both said layers,wherein the affinity of said first layer for said active substance isbetween about 1.15 and about 10 times lower than that of said secondlayer, the percent saturation of said active substance in both saidlayers being the same and being less than 100%.
 32. A transdermaldelivery device for the transdermal delivery of an active substance, forexample a pharmacologically active substance, the device having firstand second superimposed mutually contacting adhesive layers, of whichsaid first layer is pressure sensitive adhesive and is in use broughtinto contact with the skin, the active substance being dissolved in bothsaid layers, wherein the difference in drug delivery rate of said activesubstance in said first layer is between about 10% and about 100% higherthan that of said active substance in said second layer, the percentsaturation of said active substance in both said layers being the sameand being less than 100%.
 33. The transdermal delivery device of claim32, wherein the difference in drug delivery rate of said activesubstance in said first layer is between about 10% and about 87% higherthan that of said active substance in said second layer.
 34. Thetransdermal delivery device of claim 32, wherein the difference in drugdelivery rate of said active substance in said first layer is betweenabout 15% and about 60% higher than that of said active substance insaid second layer.
 35. The transdermal delivery device of claim 32,wherein the difference in drug delivery rate of said active substance insaid first layer is between about 15% and about 60% higher than that ofsaid active substance in said second layer.
 36. The transdermal deliverydevice of claim 32, wherein the difference in drug delivery rate of saidactive substance in said first layer is between about 14% and about 83%higher than that of said active substance in said second layer.
 37. Atransdermal drug-containing dosage unit which comprises a laminatecomprising: a) a backing layer substantially impervious to the drug tobe delivered transdermally; b) a first polymeric adhesive matrix, incontact with the backing layer, having dispersed therein the drug andhaving a first initial rate of delivery of the drug; c) a secondpolymeric adhesive matrix, having dispersed therein the drug and havinga second initial rate of delivery of the drug, said second polymericmatrix in contact with a release liner; and d) at least one additionaladhesive matrix, laminated in between said first and second polymericadhesive matrices, having dispersed therein the drug; each saidadditional adhesive matrix having an initial rate of delivery of thedrug; wherein said initial rates of delivery of at least two of saidmatrices are different from one another.
 38. The transdermaldrug-containing dosage unit of claim 37, wherein each of said initialrates of delivery is different from said other initial rates ofdelivery.
 39. The transdermal drug-containing dosage unit of claim 37,which comprises one additional adhesive matrix in between said first andsecond polymeric adhesive matrices, such that said additional adhesivematrix is in contact with said first adhesive matrix and with saidsecond adhesive matrix.
 40. The transdermal drug-containing dosage unitof claim 37, which comprises more than one additional adhesive matrix inbetween said first and second polymeric adhesive matrices.
 41. Thetransdermal drug-containing dosage unit of claim 37, wherein either saidfirst and second adhesive matrices or said additional adhesive matrixcomprises an acrylic adhesive.
 42. The transdermal drug-containingdosage unit of claim 41, wherein said non-acrylic adhesive matrix ormatrices comprise(s) a silicone adhesive or a polyisobutylene adhesive.43. The transdermal drug-containing dosage unit of claim 37, wherein onematrix comprises an acrylic adhesive, one matrix comprises apolyisobutylene adhesive and one matrix comprises a silicone adhesive.44. A transdermal drug-containing dosage unit which comprises a laminatecomprising: a) a backing layer substantially impervious to the drug tobe delivered transdermally; b) a first polymeric adhesive matrix, incontact with the backing layer, having dispersed therein the drug andhaving a first initial rate of delivery of the drug; c) a secondpolymeric adhesive matrix, having dispersed therein the drug and havinga second initial rate of delivery of the drug; said second polymericmatrix in contact with a release liner; and d) a third polymericadhesive matrix, in between and in contact with said first and secondpolymeric adhesive matrices, having dispersed therein the drug andhaving a third initial rate of delivery of the drug; wherein saidinitial rates of delivery of at least two of said matrices are differentfrom one another.
 45. A method for preparing a transdermaldrug-containing dosage unit comprising a laminate consisting of abacking layer, a first polymeric adhesive matrix, a second polymericadhesive matrix, a third middle polymeric adhesive matrix, and a releaseliner, said method comprising the steps of: a) providing the backinglayer substantially impervious to the drug to be deliveredtransdermally; b) providing the first polymeric adhesive matrix andlaminating it to the backing layer, wherein the first polymeric adhesivematrix has dispersed therein the drug and has a first initial rate ofdelivery of the drug; c) providing the second polymeric adhesive matrixand laminating to the release liner, wherein the second polymericadhesive matrix has dispersed therein the drug and has a second initialrate of delivery of the drug; and d) providing the third polymericadhesive matrix and laminating it to either the first or secondpolymeric adhesive matrices, wherein the third polymeric adhesive matrixhas dispersed therein the drug and has a third initial rate of deliveryof the drug; and e) laminating the combined laminate comprising thethird and first or second adhesive matrices which has resulted from step(d) to the second or first adhesive matrix, such that said thirdadhesive matrix is in between said first and second adhesive matrices;wherein said initial rates of delivery of at least two of said matricesare different from one another.
 46. A method for preparing a transdermaldrug-containing dosage unit comprising a laminate consisting of abacking layer, a first polymeric adhesive matrix, a second polymericadhesive matrix and a release liner, said method comprising the stepsof: a) providing the backing layer substantially impervious to the drugto be delivered transdermally; b) providing the first polymeric adhesivematrix and laminating it to the backing layer; c) providing the secondpolymeric adhesive matrix and laminating it to the release liner; and d)laminating the first and second adhesive matrices to one another;wherein a drug to be delivered transdermally is initially suspended ordispersed within at least one of said first and second adhesive matricesand wherein if said drug is suspended or dispersed within both of saidfirst and second adhesive matrices, said drug is initially deliveredfrom said first adhesive matrix at a rate which is different from theinitial rate of delivery of said second adhesive matrix.
 47. A methodfor administering a drug transdermally to an individual in need of suchadministration, comprising applying to skin of the individual atransdermal dosage unit comprising a laminate comprising: a) a backinglayer substantially impervious to the drug to be deliveredtransdermally; b) a first polymeric adhesive matrix, in contact with thebacking layer, having dispersed therein the drug and having a firstinitial rate of delivery of the drug; c) a second polymeric adhesivematrix, in contact with the first adhesive matrix, having dispersedtherein the drug and having a second initial rate of delivery of thedrug; and d) at least one additional adhesive matrix, in between saidfirst and second polymeric adhesive matrices, having dispersed thereinthe drug; each said additional adhesive matrix having an initial rate ofdelivery of the drug; wherein said initial rates of delivery of at leasttwo of said matrices are different from one another.